NO144110B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5: 6-BENZO-4-PYRON DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of 5:6-benzo-4-pyrone derivatives with the general formula (I)

where:

n^ is 0 or 1,

R, sitting in the 6 or 7 position, is COOR,

where R^^ is hydrogen or a

C -C19 1 12

alkyl group, which may be unsubstituted or sub-

stituted with the group

wherein each of R, • and R11 is independently hydrogen or C1-C8 alkyl, or

R^ is hydrogen or C^-C^ alkyl,

R^ is hydrogen or C^-C^ alkyl,

each of Rfi, R7 and RR is equal or different and is

hydrogen, fluorine,

above stated,

ler 1, and R'^ is a C2-C12 alkenyl or a C^-Cj2 alkyl group optionally substituted with an -OR^ group, where R^4 is hydrogen or C-^-C8 alkyl group,

X is phenyl, furyl, thienyl, pyridyl or pyrazinyl, and pharmaceutically acceptable salts thereof, provided that when at the same time X is phenyl, n-^ is 0 and R^, Rg , and Rg are all hydrogen, R is not a free carboxy group.

It should further be noted that the compounds according to formula (I) also include all possible stereoisomers as well as mixtures thereof.

In the compounds according to formula (1); is the position of the substituents in X indicated by

In the compounds according to formula (I), the alkyl, alkenyl and alkoxy groups can be branched or unbranched.

Preferably, when in the compounds of formula (I), there is a propyl or allyl group, the propyl or allyl group is in the 8-position. Preferably, when X is a phenyl group, n^ is 0 and Rg and R^ are hydrogen, Rg is different from hydrogen and is preferably substituted in the 2<1> position in the phenyl group. When m is 0, R 1 is preferably a C 1 -C 4 alkyl group, when m is 1, R 1 is preferably a C 2 -C 4 alkyl group, especially a propyl-, isopropyl-, butyl-, 1-methyl-propyl and 2-methyl-propyl group.

When R^^ is a substituted alkyl group, the substituent is preferably a hydroxy or ethoxy group.

Examples of pharmaceutically acceptable salts are sodium salts, and. salts with 2-amino-ethanol and 2-amino-2-hydroxymethyl-1,3-propahdiol.

According to the invention, the 5:6-benzo-4-pyrone derivatives can be prepared by

(a) cyclizes a compound of formula (II)

where n^, R, R^, R^, Rg, R7, Rg and X are as above, (b) reacting a compound of the general formula (III) where R and R^ are as above, with an aldehyde of the general formula (IV) wherein R 8 , R 7 , R 8 and X are as previously indicated, in which gives compounds of formula (I), wherein n 1 is 1 and R 3 is hydrogen, (c) dehydrogenates a compound of the general formula where n^, R, R^, R5, Rg, R7, Rg and X are as previously indicated, (d) cleaves a hydrogen halide from formula (VI)

wherein one of M is hydrogen and the other is halogen,

R, R,., Rg, R^, Rg and X are as previously stated,

which gives compounds of general formula (I), where n-^

is 0,

and, if desired, transfer a compound of the general formula (I) into another compound of the general formula (I) by known methods, and/or, if desired, transfer a compound of the general formula (I) into a pharmaceutical acceptable salt thereof, and/or, if desired, dissolves an obtained mixture of optical isomers into the individual isomers.

The cyclization of the compound of formula (II) is preferably carried out in the presence of acid catalysts, for example such as hydrochloric acid, hydroiodic acid, sulfuric acid, formic acid, at a temperature preferably in the range 20 - 120°C, and in an inert solvent, such as methanol, ethanol, dioxane , tetrahydrofuran, benzene, toluene, acetic acid and mixtures thereof.

Reaction of a compound of formula (III) with an aldehyde of formula (IV) is carried out in the presence of basic condensing agents, such as sodium ethoxide, sodium methoxide, sodium hydride, sodium amide, sodium or potassium hydroxide, in temperature ranges preferably between 0 and 100°C, and in a solvent preferably selected from the group consisting of methanol, ethanol, dioxane, water and mixtures thereof.

The dehydrogenation of the compound of the general formula (V) is preferably carried out with Se0 2 in an organic solvent, such as toluene, xylene or N-amyl alcohol at the reflux temperature. The dehydrohalogenation of a compound of the formula (VI) is preferably carried out by treatment with a base, preferably selected from the group comprising NaOH, KOH, I^CO^, potassium tert-butylate, pyridine, triethylamine, in an organic solvent, selected for example from the group consisting of ethanol, acetone, dimethylformamide and dimethylsulfoxide, at a temperature in the range from room temperature to the reflux temperature.

A compound of the general formula (I) can be converted, as indicated above, into another compound of the general formula (I) by known methods.

For example, a compound of the general formula (I), in which R is a carboxy group, can be converted into a compound of the general formula (I), in which R is a carboxyl group by esterification, for example by reacting an alkaline salt of the acid with the desired alkyl halide.

A compound of formula (I) in which R is a carboxy group can be converted into a compound of formula (I) in which R is the tetrazolyl group of the formula

by known methods, for example by converting the carboxy group into the corresponding halide, preferably chloride, for example by reacting with thionyl chloride in benzene at the reflux temperature, and then reacting the obtained halide, for example with ammonia, to give the corresponding amide, after which the amide is dehydrated to the corresponding nitrile, for example using p-toluenesulfonyl chloride in pyridine, and finally the nitrile is reacted with sodium azide and ammonium chloride in dimethylformamide at a temperature varying between room temperature and 100°C.

The possible salt formation of the compounds of formula (I) can also be carried out according to known methods.

The compounds of formula (TI) can be prepared by reacting a compound of formula (VII)

wherein R, and R,, have the previously indicated

meanings,

with a compound of formula (VIII)

wherein nlfR3, Rfi, R?, Rg and X have the previously indicated meanings and

R 1 is an aryl group, preferably phenyl or alkyl.

The reaction between the compound of formula (VII) and the compound of formula (VIII) is preferably carried out in an organic solvent, such as methanol, ethanol, dioxane and pyridine, in the presence of a strong base, for example such as sodium methoxide, sodium ethoxide, sodium hydride, at a temperature in the range from room temperature to the reflux temperature.

An alternative method for preparing the compound of formula (II) comprises reacting, by known methods, a compound of formula (VII) with a compound of formula (IX) in which M' is halogen or a hydroxy group, and n^, R^ , Rg, Ry, Rg and X have the previously indicated

meanings,

to give a compound of formula (X)

wherein n1# R, R3, Rg, Rg, R?, Rfl and X

have the previously stated meanings,

and then re-lay the connections off

formula (X) in an inert solvent,

e.g. pyridine, toluene, methyl ethyl ketone, in the presence of a strong base, for example sodium, sodium amide, potassium hydroxide, potassium carbonate, at a temperature varying from room temperature to the reflux temperature.

The compounds of formula (III) can, for example, be prepared by acidic cyclization of p-diketones of the general formula (XI)

wherein R 1 and R 5 are as previously indicated

meanings,

which in turn can be produced by a basic condensation of an acetic acid ester, such as a methyl acetate, ethyl acetate, phenyl acetate with a substituted ortho-hydroxy-acetophenone of the general formula (VII), preferably by carrying out the reaction in the range 20 - 100°C, in the absence of solvents or in a solvent preferably selected from the group consisting of benzene, toluene, dioxane and mixtures thereof, using sodium hydride as condensing agent.

The compound of formula (VII) can, for example, be prepared from suitably substituted phenols by means of a Friedel-Crafts condensation or by a Fries inversion.

The compounds of formula (V) can be prepared using starting compounds of the general formula (XII)

wherein n]L, R, R3, ^5,\, R?, R8 and X

have the previously stated meanings,

by reaction with basic condensing agents, such as sodium or potassium hydroxide, sodium amide, sodium hydride, sodium or potassium carbonate, potassium acetate or acids, for example

hydrohalic acids, sulfuric acid, phosphoric acid, p-toluenesulfonic acid in solvents, for example methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, dimethylsulfoxide, at a temperature varying in the range from room temperature to reflux temperature.

Compounds of formula (XII), in turn, can be prepared by condensing a compound of formula (VII) with a substituted aldehyde of formula (XIII)

where n1? R3, Rg, R?, Rg and X have the meanings previously indicated.

The condensation can be carried out in a deionising medium1, for example selected from the group consisting of methanol, ethanol, dioxane, water and mixtures thereof, in the presence of a basic catalyst,

such as pyridine, sodium hydroxide, sodium hydride, sodium alkoxide at temperatures in the range from room temperature to the reflux temperature.

The compounds of formula (VI) can be prepared by halogenation of compounds of formula (V) with, for example, N-bromosuccinimide or pyridine perbromide [(N,B. Lorette et al., J. Org. Chem., 16, 930 (1951)$ S .Hishide et al, J. Chem. Soc. Japan, 74, 697 (1953)].

The compounds produced according to the invention show anti-allergic activity, as shown by the fact that they are active in passive cutaneous anaphylaxis (PCA) in rat experiments, according to Goose Y. and Blair A.M.Y.N. (Immunology, 1969, 16:749). The

can therefore be used in the prevention and treatment of bronchial asthma

asthma, allergic rhinitis, hay fever, urticaria and dermatosis. An important characteristic of the new connections is also that they

exhibit anti-allergic activity when administered orally.

The following table shows the protection obtained with the compounds produced according to the invention when administered orally in the PCA test in rats, compared to well-known antiallergic agents, for example disodium cromoglycate (DSCG)

and AH 7725, i.e., 2-carboxy-7-hydroxyethoxy-xants1oh (Fullarton, J., Martin, L.E., and Vardey, C., Int. Arch. All., 1973, 45:84).

The following table shows the activity values obtained in the PCA test on rats after oral administration for several compounds according to the present invention, which compounds are identified by the codes K 10142, K 10222, K 10149, K 11047, K 11056, K 11006, K 10175, K 11071, K 11662, K 11785, K 11190, K 11936, K 11179, K 11078, K 11087, K 11088, K 11080, K 11074, K 11054, K 11089, K 11166, K 11202, K0, K 11648 K 11602, K 11152.

The activity data are expressed as K expressed as the dose (mg/kg) of active compound that can reduce to half the activity of the serum used for sensitization:

where

B = dose of antagonist compound expressed in mg/kg,

DR = dosage ratio: antilogarithm of the distance between the serum curve with and without antagonist (J.H.Gaddum et al, Exp.

Physiol., 1955, £0, 49),

as KB is equal to the antilog

which is independent both of the dosage

of the compound and concentration of reagent used affects sensitization. pA2 is the negative logarithm of the molar concentration of an antagonist (A) that reduces the effect of a stimulant drug by half.

The lower is the K value and the higher is the anti-allergic activity. In the following table, the antiallergic activity of the compound according to the invention is compared with the corresponding effect of disodium chromium glycate (DSCG), a well-known antiallergic compound.

In the following table, the connections are indicated by the codes:

K 10142: 6-carboxy-4'-isopropyl-flavone;

K 10222: 6-carboxy-2'-methoxy-flavone;

K 10149: 6-carboxy-2<1->isopropoxy-flavone;

K 11047: 6-carboxy-2'-allyloxy-flavone;

K 11056: 6-carboxy-2'-butoxy-flavone;

K 11006: 6-carboxy-2<1->(2-ethoxy-ethoxy)-flavone;

K 10175: 6-carboxy-41-(2-ethoxy-ethoxy)-flavone;

K 11071: 6-carboxy-2'-(2-hydroxy-propoxy)-flavone;

K 11662: 6-carboxy-4<1->fluoro-flavone;

K 11785: 6-carboxy-3<1->fluoro-flavone;

K 11190: 6-carboxy-2<1->dimethylamino-flavone;

K 11936: 6-carboxy-2'-isopropoxy-5'-methyl-flavone;

K 11179: 6-carboxy-2<1->isopropoxy-flavone 2-dimethylamino-ethyl ester;

K 11078: 6-carboxy-2-[3-(2'-methoxyphenyl)-vinyl]-chromone;

K 11087: 6-carboxy-2-(α-methyl-3-phenyl-vinyl)-chromone;

K 11088: 6-carboxy-2-(2'-furyl)-chromone;

K 11080: 6-carboxy-2-(2'-thienyl)-chromone;

K 110 74: 6-carboxy-2-(2'-pyridyl)-chromone;

K 11054: 6-carboxy-2-(3'-pyridyl)-chromone;

K 11089: 6-carboxy-2-(2'-pyrazinyl)-chromone;

K 11166: 6-carboxy-2-(5'-methyl-2'-pyrazinyl)-chromone;

K 11202: 6-carboxy-2-(6'-methyl-2'-pyrazinyl)-chromone;

K 11648: 6-carboxy-8-propyl-2-(2'-pyrazinyl)-chromone;

K 11650: 6-(5-tetrazolyl)-2-(2'-pyrazinyl)-chromone;

K 11602: 6-[2-(N,N-diethylamino)-ethoxy-carbonyl]-2-(2'-pyrazinyl)-chromone;

K 11152: 6-[2-(N,N-diethylamino)-ethoxy-carbonyl]-2'-isopropoxy-flavone.

The antiallergic activity was determined by the inhibition of IgE-dependent PCA according to Goose J. and Blair A.M.J.N. (Immunology, 1969, 16 : 749) by using homocytotropic antibodies

called in rats according to the method of Mota I., Immunology, 1_, 681,

(1964).

The examined compounds were given per us 15 min. before the administration of the antigen and at least 6 rats were used for each determination.

In addition to the anti-allergic activity, the compounds produced according to the invention are effective in reducing resistance in the airways and increasing lung capacity, and can therefore be used in the treatment of respiratory failure, for example in acute lung failure, as shown by results obtained for rats under application of the technique described by Palecek F., Palecekova M., and Aviado D.M. (Arch. Environ. Health, 1967, 15: 332-342). By these

experimentally, the compounds produced according to the invention, especially 6-carboxy-2'-isopropoxy-flavone, lower airway resistance and increase lung capacity even at doses as low as 4 mg/kg/i.v., and at the same dose they counteract (50%) the bronchial constricting effect of 5-HT ( = 5-hydroxy-tryptamine, i.e. serotonin) and of compound 48.80 (histamine-releasing drug).

The compounds produced according to the present invention exhibit external

higher anti-ulcer activity, as shown by the fact that they were shown to be active in inhibiting stress-induced ulcers in rats kept in a water bath at 25°C for 40 min. according to a modification of the technique described by Takagi,

K. and Okabe, S. (Jap. J. Of Pharmac, 1968, 18:9).

In this experiment, the compounds produced according to the invention, in particular the 6-carboxy-2'-isopropoxy-flavone sodium salt, showed 45% inhibition of stress-induced ulcers in rats, when administered

treated dose of 50 mg/kg/i.v.

The compounds produced according to the present invention can be administered in a conventional manner, for example orally or parenterally in daily doses, preferably of 0.5 - 15 mg/kg, or by inhalation, preferably in daily doses of 0.5 - 100 mg, preferably 0.5 - 25 mg, or by topical applications.

The type of pharmaceutical preparations containing the compounds produced according to the present invention together with pharmaceutically acceptable carriers or diluents will naturally depend on the intended method of administration.

The compounds can be mixed in a conventional manner with the usual ingredients. For example the compounds produced according to the invention can be administered in the form of aqueous or oily solutions or suspensions, aerosols, as well as powders, tablets, pills, gelatin capsules, syrups, or creams or solutions for topical application.

The following examples illustrate the invention.

EXAMPLE 1

A solution of methyl 3-acetyl-4-hydroxybenzoate (60 g) and methyl 2-isopropoxybenzoate (120 g) in dioxane (400 ml) was slowly added with stirring at room temperature to a suspension of sodium hydride 50% (45 g) in dioxane (200 ml). The mixture was kept for 4 hours at 80°C, cooled and then diluted with petroleum ether (600 ml), then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with sodium carbonate (5%) and water, and then evaporated to dryness and recrystallized from ethanol to give (2-hydroxy-5- carbomethoxy-benzoyl)-(2-isopropoxy-benzoyl)-methane (70 g); m.p. 105 - 107°C), which was then refluxed for 15 min. with 99% formic acid (280 ml). After cooling and dilution with water (1 L) and filtration, the collected precipitate was recrystallized from acetone to give 6-carbomethoxy-2'-isopropoxy-flavone (60 g, mp 154-155°C), which was hydrolyzed with a solution of potassium hydroxide (1%) (1. 1.020) in 95% ethanol at the reflux temperature

for 30 min. The mixture was cooled, acidified with acetic acid and evaporated under vacuum to give a precipitate which was filtered off, washed with ethanol (95%) and water to give, after recrystallization from ethanol, 6-carboxy-2'-isopropoxy-flavone (45 g; m.p. 209 - 211°C).

By applying the same technique, the following compounds were obtained: - 6-carboxy-2'-propoxy-flavone, m.p. 201 - 203°C^ - 6-carboxy-2'-(2-methyl-propoxy)-flavone, m.p. 193 - 195°C5 - 6-carboxy-2'-butoxy-flavone, m.p. 204 - 206°C5 - 6-carboxy-2'-ethoxy-flavone, m.p. 225 - 227°C$ - 6-carboxy-2'-methoxy-flavone, m.p. 265 - 267°C$ - 6-carboxy-2' 6'-dimethoxy-flavone, m.p. >300°C; I.R.(KBr): V"c=0 (carboxy) 1715 cm 1, YC=Q (chromone) 16 40 cm 1 - 6-carboxy-2'-(1-methyl-propoxy)-flavone; mp 186-188 °C;

- 6-carboxy-2'-allyloxy-flavone, m.p. 193-196°C

- 6-carboxy-2'-isopropyl-flavone, m.p. 218-221°C<N>

- 6-carbomethoxy-2'-propoxy-flavone, m.p. 211-213°C; - 6-carbomethoxy-2 1 -(2-methyl-propoxy)-flavone, m.p. 147-150°C; - 6-carbomethoxy-2'-allyloxy-flavone, m.p. 111-114°C; - 6-carbomethoxy-21-(1-methyl-propoxy)-flavone. mp<p.> 132-135°C; - 6-carbomethoxy-2',6<1->dimethoxy-flavone, m.p. 189-192°C; - 6-carboxy-4'-isopropoxy-flavone, m.p. 263-265°C; - 6-carboxy-3'-isopropoxy-flavone, m.p. 235-237°C; - 6-carboxy-4'-isopropyl-flavone, m.p. 250-253°C; - 6-carbomethoxy-2',4'-dimethoxy-flavone, mp, 210-213°C; - 6-carboxy-2', 4'-dimethoxy-flavone, m.p. ~.320°C; - 6-carboxy-3',4<1->dimethoxy-flavone, m.p. 302-304°C; - 6-carbomethoxy-2'-isopropoxy-4'-methoxy-flavone, m.p. 178-180°C;

- 6-carboxy-2<1->isopropoxy-4'-methoxy-flavone, m.p. 303-305°Cj

- 6-carbomethoxy-2'-isopropoxy-4'-(2-ethoxy-ethoxy)-flavone,

m.p. 132-134°C

- 6-carboxy-2'-isopropoxy-4'-(2-ethoxy-ethoxy)-flavone, m.p. 179-181°C; - 6-carboxy-2'-(2-ethoxy-ethoxy)-flavone, m.p. 198-200°C; - 6-carboxy-2'-(2-hydroxy-propoxy)-flavone, m.p. 210-212°C;

- 6-carboxy-2'-(1-methyl-2-N,N-dimethylamino-ethoxy)-flavone,

m.p. 120°C (decomposition); - 6-carboxy-2'-(2-N,N-diethylamino-ethoxy)-flavone, m.p. 204-206°C;

- 6-carboxy-4'-(2-ethoxy-ethoxy)-flavone, m.p. 122-124°C.

and starting from 3-hydroxy-4-acetyl-benzoate, the following was obtained: 7-carboxy-2'-isopropoxy-flavone, m.p. 282-284°C; 7-carbomethoxy-2<1->isopropoxy-flavone, mp 122-124°C

Starting from ethyl 3-acetyl-4-hydroxy-benzoate, the following compounds were obtained•

6-carbethoxy-2'-isopropoxy-flavone, m.p. 107-108°C; 6-carbethoxy-2-(2'-pyrazinyl)-chromone, m.p. 168-169°C;

EXAMPLE 2

A solution of methyl 3-acetyl-4-hydroxybenzoate (54 g) and

methyl 2-benzyloxybenzoate (135 g) in dioxane (400 ml) was

slowly added, with stirring at room temperature, to a suspension of sodium hydride (50%, 40 g) in dioxane (150 ml). The mixture was kept for 5 hours at 70°C, then cooled and diluted with petroleum ether, and then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with potassium carbonate, 5%, and water, then evaporated to dryness. After crystallization from methanol, (2-hydroxy-5-carbomethoxy-benzoyl)-(2-benzyloxy-benzoyl)-methane (74 g; mp 95 - 97 °C) was obtained, which was then refluxed for 24 h with formic acid ( 99%, 500 ml). After cooling and diluting with ethanol (500 mL), the precipitate obtained was filtered and washed with ethanol to give 6-carbomethoxy-2'-hydroxy-flavone

(31 g5 m.p. 290-291°C), which was then reacted in dimethylformamide (150 ml) with 1-chloro-2-benzoyloxy-propane (26 g) and potassium carbonate (18 g) at 70°C for 16 hours. The mixture was cooled, diluted with water (600 mL), filtered, and then washed with water to give 6-carbomethoxy-2'-(2-benzoyloxy-propoxy)-flavone (45 g), which was hydrolyzed with a solution of potassium hydroxide, 1%, (1.1.250) in ethanol (95%)

at reflux temperature for one hour. After cooling, acidifying with acetic acid, concentrating to a small volume under vacuum and diluting in water, the precipitate obtained was filtered, then washed with water to give, after crystallization with methylene chloride/ethyl acetate 6-carboxy-21-(2-hydroxy- propoxy)-flavone (18.5^ m.p. 211 - 213°C.

Proceeding in an analogous manner, the following compounds were obtained:

- 6-carboxy-2'-(2-hydroxy-ethoxy)-flavone, m.p. 238 - 240°C.

- 6-carboxy-2'-(3-hydroxy-propoxy)-flavone, m.p. 215-217°C;

- 6-carboxy-2'-(2-hydroxy-3-methyl-butoxy)-flavone,

- 6-carboxy-21-(2,3-dihydroxy-propoxy)-flavone, m.p. 213-216°C; - 6-carboxy-4'-(2-hydroxy-ethoxy)-flavone, m.p. 309-312°C.

EXAMPLE 3

6-Carbomethoxy-2'-hydroxy-flavone (5 g), obtained according to the method described in Example 2, was reacted in dimethylformamide (30 ml) with (3-ethoxy-ethyl bromide (3.5 g) and potassium carbonate (3.2 g) at 80°C for 16 h. The mixture was cooled, diluted in water, filtered, washed with water. After crystallization from methanol, 6-carbomethoxy-21-(2-ethoxy-ethoxy)-flavone (4 .5 g) was obtained, which was hydrolyzed with a solution of potassium hydroxide (1%, 90 ml) in ethanol (95%) at the reflux temperature for 45 minutes.

Subsequently, after cooling, acidification with acetic acid, concentration, dilution with water, filtration and crystallization from ethanol gave 6-carboxy-2'-(2-ethoxy-ethoxy)-flavone (3.1 g; mp 198-200°C ).

By using the suitable alkyl halides, the following compounds were prepared: - 6-carboxy-2'-isopropoxy-flavone, m.p. 208-210°C; - 6-carboxy-21-(2-methyl-propoxy)-flavone, m.p. 192-194°C; - 6-carboxy-21-(2-hydroxy-propoxy)-flavone, m.p. 210-212°C; - 6-carboxy-21-(1-methyl-propoxy)-flavone, m.p. 186-188°C; - 6-carboxy-2'-(2-hydroxy-2-methyl-propoxy)-flavone; - 6-carboxy-21-(2-hydroxy-2-methyl-butoxy)-flavone; - 6-carboxy-2'-(2,3-dihydroxy-propoxy)-flavone, m.p. 213-216°C; - 6-carboxy-2'-(1-methyl-2-N,N-dimethylamino-ethoxy)-flavone. m.p. 120 oC (decomposition) - 6-carboxy-2'-(2-N,N-diethylamino-ethoxy)-flavone, m.p. 204-206°C; and in the same way, starting from 6-carbomethoxy-4'-hydroxy-flavone, the following compounds were obtained: - 6-carboxy-4'-(2-ethoxy-ethoxy)-flavone, m.p. 221-223°C; - 6-carboxy-4'-(2-hydroxy-ethoxy)-flavone, m.p. 309-312°C;

EXAMPLE 4

Methyl-3-acetyl-4-cinnamoyloxybenzoate (46.2 g; m.p. 97-99°C) was dissolved in methyl ethyl ketone (350 ml). After addition of anhydrous potassium carbonate (37 g), the mixture was refluxed treated for 6 h. After cooling, diluting with petroleum ether (500 ml) and filtering, the collected precipitate was dissolved in water, acidified with acetic acid, extracted with ethyl acetate. The organic phase was washed with potassium carbonate

(5%) and water, and then evaporated to dryness. After crystallization from methanol, (2-hydroxy-5-carbomethoxy-benzoyl)-cinnamoyl-methane (31.2 g; mp 138 - 140 °C) was obtained, which was refluxed for 15 min with formic acid (99%) (140 ml). After cooling, diluting with water (1 1) and filtering, the collected precipitate was crystallized from acetone to

give 6-carbomethoxy-2-((3-phenylvinyl)-chromone (27.8 g, m.p. 175-177°C), which was hydrolyzed with a solution of potassium hydroxide 1% (600 ml) in ethanol, 95 %, at reflux temperature for 45 min. After cooling, acidification with acetic acid, concentration under vacuum and dilution with water, the precipitate was collected and washed with water to give, after crystallization from acetone, 6-carboxy-2-(@-phenyl-vinyl) -chromone (16.1 g; mp 273 - 275°C).

By using the suitable esters of methyl 3-acetyl-4-hydroxy-benzoate, the following compounds were prepared: - 6-carboxy-2-(a-methyl-3-phenyl-vinyl)-chromone, m.p. 220 - 222°C$ - 6-carboxy-2-(|3-2'-methoxy enyl-vinyl)-chromone, m.p. 270°C (decomposition); - 6-carboxy-2-[3-(3'-pyridyl)-vinyl]-chromone, m.p. >350°C; I.R.

(KBr) : ^ C=Q (carboxy) 1710 cm"<1>, ^r=f) (chromone) 1655 cm"<1>,

1640 cm <1>, Y (trans ,

- 6-carbomethoxy-2-(o-methyl-p-phenyl-vinyl)-chromone, m.p. 147-151 C; - 6-carbomethoxy-2-(3-2'-methoxy-phenyl-vinyl)-chromone, m.p. 186-187°C; - 6-carboxy-2-(3-3'-methoxy-phenyl-vinyl)-chromone, m.p. 271-273°C; - 6-carboxy-2-(3-4'-methoxy-phenyl-vinyl)-chromone, m.p. 280-282°C; - 6-carboxy-2-(3~4 1-methyl-phenyl-vinyl)-chromone, m.p. > 320°C; - 6-carboxy-2-(3-4'-fluoro-phenyl-vinyl)-chromone, m.p. >300°C; - 6-carbomethoxysv~2-(3-4'-fluoro-phenyl-vinyl)-chromone, m.p. 193-195°C;

oq in the same way starting from 3-cinnamoyloxy-4-acetvl-ben-

zoate (m.p. 91-94°C-the following compounds were obtained:

- 7-carboxyl-2-(3-phenyl-vinyl)-chromone, m.p. 272-273°C;

- 7-carbomethoxy-2-(3-phenyl-vinyl)-chromone, m.p. 171-172°C.

By proceeding as described above and starting from methyl-3-acetyl-4-(4'-fluoro-benzoyloxy)-benzoate, the following compounds were obtained:

- 6-carbomethoxys-4'-fluoroflavone, m.p. 218-220°C:

- 6-carboxy-4'-fluoro-flavone, m.p. 297-299°C;

In saran fashion was produced:

- 6-carboxy-3'-fluoroflavone, m.p. 314-316°C.

EXAMPLE 5

Using the method described in Example 4,

starting from methyl 3-acetyl-4-(ortho-benzoyloxy-cinnamoyl-oxy)-benzoate and hydrolyzing the benzyl ether group by heating

ning at reflux temperature for 24 hours with an excess of formic acid, 99%, became 6-carbomethoxy-2-(3_2<1->hydroxyphenyl-vinyl)-

chromone obtained (m.p. 252-254°C), after crystallization from

acetone. This product (7 g), dissolved in dimethylformamide (35 ml) was reacted with (3-ethoxy-ethyl bromide (4.2 g) and anhydrous potassium carbonate (4 g) at 70°C for 24 h. After cooling, dilution with water and filtration, the collected precipitate was hydroly

served with the stoichiometric amount of potassium hydroxide (1%)

i.ethanol (95%) at reflux temperature for one hour. After cooling, dilution with water, acidification with citric acid, the precipitate was collected and crystallized from methanol/benzene, to

give 6-carboxy-2-[3-2'-(2-ethoxy-ethoxy)-phenyl-vinyl | -chromone (3.6 g; m.p. 218°C decomposition).

By using the appropriate alkyl halides, the following compounds were obtained:

- 6-carboxy-2-[lf-2'(2-hydroxy-niropoxy)-phenyl-vinyl]-chromone

m.p. 231-235°C;

- 6-carboxy-2-(fl-2'-isopropoxy-phenyl-vinyl)-chromone, m.p. 246- 248°C; and in the same way, starting from methyl 3-acetyl-4-(para-benzoyl-oxy-cinnamoyloxy)-benzoate, the following compounds were obtained: - 6-carboxy-2-(fl-41-hydroxy-phenyl- vinyl)-chromone, m.p. 337-338°C; - 6-carbomethoxy-2-(fl-4'-hydroxy-phenyl-vinyl)-chromone, m.p. 316-317°C; - 6-carboxy-2-(fl-4'-isopropoxy-phenyl-vinyl)-chromone, m.p. 245-246°C; - 6-carbomethoxy-2-(fl-4'-isopropoxy-phenyl-vinyl)-chromone, m.p. 134-136°C; - 6-carboxy-2-[fl-4'-(2-ethoxy-ethoxy)-phenyl-vinyl]-chromone, m.p. 248-249°C;

- 6-carbomethoxy-2-[fl-41-(2-ethoxy-ethoxy)-phenyl-vinyl]-chromone,

m.p. 146-147°C.

EXAMPLE 6

A solution consisting of methyl 3-acetyl-4-hydroxy-benzoate

(16 g) and methyl nicotinate (23 g) in dioxane (100 ml) were. slowly added at room temperature with stirring to a suspension of sodium hydride, 50%, (12 g) in dioxane (60 ml). The solution was kept for 6 hours at 80°C, then cooled, diluted with petroleum ether (200 mL), and filtered. The product obtained was dissolved in water and treated with acetic acid. The precipitate obtained was washed with water and crystallized with methylene chloride/methanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-nicotinoylmethane (17.2 g, m.p. 200-202°C), which was then treated with ethanol (300 ml), containing concentrated hydrochloric acid (1%) at reflux temperature for 2 hours. After concentration under vacuum, dilution with water, neutralization

tion with sodium acetate, the precipitate was filtered. The crude 6-carbomethoxy-2-(3'-pyridyl)-chromone (15.1 g) was hydrolyzed with the stoichiometric amount of potassium hydroxide (1%) in ethanol,

95%, at reflux temperature for one hour. After cooling, diluting with water (600 ml), neutralizing with acetic acid, the precipitate was collected to give, after crystallization from dimethylformamide, 6-carboxy-2-(3'-pyridyl)-chromone (9.8 g^ m.p.

>350°C)-, I.R. (KBr): Vc=0 (carboxy) 1680 cm <1>, V c=0

(chromone) 1630 cm<-1>, 1610 cm<-1>, 6 (meta-substituted

-1 -1

pyridine) 770 cm , 696 cm

Proceeding in an analogous manner, the following compounds were prepared:

- 6-carboxy-2-(2'-pyridyl)-chromone, m.p. >300°C; I.R. (KBr):

V (carboxy) 1710 cm<-1>, V (chromone) 1650 cm<-1>,

c—o ^— ^ ^

6_, (ortho-substituted pyridine) 768 cm

C—H q

- 6-carboxy-2-(4'-pyridyl)-chromone, m.p. >350 C; I.R. (KBr):

V c=0 (carboxy) 1690 cm<-1>, v c=0 (chromone) 1630 cm<-1>,

6„ „ (para-substituted pyridine) 825 cm ^

C—H

- 6-carboxy-2-(2'-thienyl)-chromone, m.p. 301 - 304°C$

- 6-carboxy-2-(2'-furyl)-chromone, m.p. 330 - 332°C;

- 6-carboxy-2-(2'-pyrazinyl)-chromone, m.p. 350°C;_I.R. (KBr):

V c=0 (carboxy) 1695 cm , Vc=0 (chromone) 1645 cm

- 6-carboxy-2-{3'-isopropoxy-2'-pyridyl)-chromone; m.p. 285-288°C - 6-carboxy-2-(3<1->methoxy-2'-pyridyl)-chromone, m.p. 322-324°C; - 6-carboxyl-2-(6'-methyl-2'-pyrazinyl)-chromone, m.p. 320°C (split.) I.R. (KBr): Vc=0 (carboxy) 1700 cm"<1>, ^ c=0 (chromone) 1655 cm"<1>; - 6-carboxy-2-(5<1->methyl-2<1->pyrazinyl)-chromone, m.p. 316-319°C;

- 6-carboxy-2-(3'-pyridazinyl)-chromone, m.p. >320°C: I.R.

(KBr): VC=Q (carboxy) 1700 cm"<1>, VC=Q (chromone) 1635 cm"<1>;

- 6-carbomethoxy-2-(2'-pyridyl)-chromone, m.p. 194-196°C; - 6-carbomethoxy-2-(3'-pyridyl)-chromone, m.p. 211-213°C; - 6-carbomethoxy-2-(4<1->pyridyl)-chromone, m.p. 207-210°C; - 6-carbomethoxy-2-(2-thienyl)-chromone, m.p. 194-196°C; - 6-carbomethoxy-2-(2<1->furyl)-chromone, m.p. 226-229°C; - 6-carbomethoxy-2-(2'-pyrazinyl)-chromone, m.p. 232-234°C; - 6-carbomethoxy-2-(3'-methoxy-2<1->pyridyl)-chromone, m.p. 203-205°C; - 6-carbomethoxy-2-(3'-isopropoxy-2'-pyridyl)-chromone, m.p. 154-57°C; - 6-carbomethoxy-2-(6'-methyl-2'-pyrazinyl)-chromone, m.p. 204-206°C; - 6-carbomethoxy-2-(5'-methyl-2'-pyrazinyl)-chromone, m.p. 240-242°C;

Starting from a methyl 3-hydroxy-4-acetyl-benzoate, the following compounds were obtained: - 7-carboxy-2-pyrazin-2'-yl-chromone, m.p. > 340°C;

Starting from ethyl 3-acetyl-4-hydroxybenzoate, the following compound was obtained:

- 6-carbethoxy-2-(2'-<p>yrazinyl)-chromone, m.p. 168-169°C.

EXAMPLE 7

By proceeding in the same way as described in example 5 f out-

starting from methyl-3-hydroxy-4-acetyl-benzoate, the following compounds were obtained: - 7-carboxy-2-(2'-furyl)-chromone; (m.p. >340°C, I.R. (KBR):^q_q

-ti i-i -» • -i \ i •* icarboxy) 1705 cm~l Vr_n ;- 7-carboxy-2-(2'-pyrazrnyl)-chromone; <*>|chromone)<Y>1640 cm-l C~°

EXAMPLE 8

By proceeding in the same way as in example 1, starting from methyl-3-acetyl-4-hydroxy-benzoate and from pure methyl-N-alkyl and N,N-dialkyl anthranilate, the following compounds were obtained: - 6- carboxy-2<1->dimethylamino-flavone; m.p. 177-181°C - 6-carbomethoxy-2'-N-methylamino-flavone, m.p. 200-203°C - 6-carboxy-2-N-ethylamino-flavone, m.p. 302-305°C; - 6-carbethoxy-2'-N-ethylamino-flavone, m.p. 165-168°C; - 6-carbomethoxy-2'-N,N-dimethylamino-flavone, m.p. 142-146°C;

- 6-carboxy-2'-amino-flavone, m.p. } 300°C.

EXAMPLE 9

By proceeding in the same way as in examples 2 and 3, outgoing

from the intermediate products methyl 3-acetyl-4-hydroxy-5-allyl-benzoate (m.p. 106 - 108°C), and methyl 3-acetyl-4-hydroxy-5-propyl-benzoate (m.p.

89 - 91°C) prepared according to the methods described in J. Pharm. Soc. Japan, 74, 47 (1954) the following compound was obtained: - 6-carboxy-8-propyl-2'-isopropoxy-flavone, m.p. 205 - 207°C;

EXAMPLE 10

By using the same procedure as described in the example

6, starting from the same intermediates as in example 9, the following compounds were prepared: - 6-carboxy-8-propyl-2-(2'-pyrazinyl)-chromone, m.p. 269-271°C - 6-carbomethoxy-8-propyl-2-(21-pyrazinyl)-chromone, m.p. 206-207°C.

EXAMPLE 11

To a solution consisting of 2-methyl-6-carbethoxychromone

(5 g) and 3-pyridyl-carboxy-aldehyde (5.5 g) in abs. ethanol (100 ml) became a solution of sodium (0.5 g) in ethanol (50

ml) slowly added with stirring at 0°C. The mixture was kept for 2 hours at room temperature, then acidified with acetic acid, concentrated under vacuum, diluted with water and finally the precipitate was collected to give, after crystallization from methanol, 6-carbomethoxy-2-(3-3<1- >pyridyl-vinyl)-chromone (3.8 g; mp 170 - 180°C), which was hydrolyzed with the stoichiometric amount of a solution of potassium hydroxide

(1%) in ethanol (95%) at reflux temperature for one hour. After cooling, dilution with 10% aqueous monobasic sodium phosphate gave a precipitate, which was collected by filtration and crystallized from N,N-dimethylformamide/methanol to give 6-carboxy-2-(3-3'-pyridyl- vinyl)-chromone (1.8 g; m.p. ^> 350°C)^

I.R. (KBr): 1640 cm<-1>,

(chromon) 1655 cm ,

Proceeding analogously, the following compounds were prepared:

- 6-carboxy-2-(3_3<1->methoxy-phenyl-vinyl)-chromone, m.p. 271-273°C; - 6-carboxy-2-(3-4'-methoxy-phenyl-vinyl)-chromone, m.p. 280-282°C;

- 6-carboxy-2-(3~4<1->methyl-phenyl-vinyl)-chromone, m.p. > 320°C^

- 6-carboxy-2-(3-4'-fluoro-phenyl-vinyl)-chromone, m.p. > 300°Cy-- 6-carbomethoxy-2-(3-4'-fluoro-phenyl-vinyl)-chromone, m.p. 193-195°C; Moreover, starting from 2-methyl-7-carbethoxy-chromone it became

the following compound obtained:

- 7-carboxy-2-(B-phenyl-vinyl)-chromone, m.p. 272-273°C.

EXE MPEL 12

Piperidine (200 ml) was added to a solution consisting of methyl 3-hydroxy-4-acetyl-benzoate (15 g) and 2-isopropoxy-benz-

aldehyde (15 g) in absolute ethanol (400 ml). After cooling, acidification with hydrochloric acid and extraction with ethyl acetate, the organic phase was washed with K 2 CO 3 (5%) and with water and then

evaporated to dryness. The residue obtained (11 g) was dissolved in n-amyl alcohol (200 ml) by the addition of SeO 2 (11 g) and the solution was kept at reflux temperature for 18 hours. After cooling, the residue was filtered off and the amyl alcohol was distilled in a stream of steam: the residue of the distillation was recovered by extraction with chloroform to give, after crystallization from isopropyl ether, 7-carbomethoxy-2<1->isopropoxy-flavone (6, 3 g), m.p. 122-124°C, which was subsequently hydrolysed by treatment with the stoichiometric amount of a solution of potassium hydroxide (1%) in ethanol (95%) at reflux temperature for 30 minutes. After cooling, acidification with acetic acid, dilution with water, filtration, and subsequent crystallization from acetone, 7-carboxy-2<1->isopropoxy-flavone, m.p. 282-284°C (4.7 g) obtained.

EXAMPLE 13

A mixture, consisting of ethyl-3-acetyl-4-hydroxy-benzoate

(6 g) and 2-nitro-benzaldehyde (5 g), dissolved in ethanol (100 ml) and piperidine (100 ml) were kept at reflux temperature for 24 hours. The mixture was then cooled, diluted with water (800 ml), acidified with hydrochloric acid, extracted with ethyl acetate, washed with water and evaporated to dryness to give the crude product, 6-carbomethoxy-2'-nitro-flavanone. This product (6.8 g) was dissolved in chloroform (40 ml) and treated with a solution of benzoyl peroxide (0.15 g) and N-bromosuccinimide (3.8 g) dissolved in chloroform (60 ml). The mixture was kept at reflux for 4 hours, then evaporated to dryness under vacuum at low temperature. Then the residue, dissolved in ethanol (95%) (150 ml), was treated with sodium hydrate 4 N (25 ml) at room temperature overnight. After acidification with hydrochloric acid and filtration, 6-carboxy-2'-nitro-flavone (3.7 g), m.p. 238-241°C/ obtained, which was then treated with stannous chloride (20 g) in concentrated hydrochloric acid (15 ml) and glacial acetic acid (15 ml) at reflux temperature for 4 hours. After cooling, dilution with water, neutralization with ammonium hydrate 28 Bé, the precipitate was filtered to give, after crystallization from dimethylformamide, 6-carboxy-2'-amino-flavone (1.8 g, m.p. >300°C).

EXAMPLE I4

6-Carboxy-2'-isopropoxy-flavone (21 g), suspended in 1,2-dichloroethane (75 ml) was treated with thionyl chloride (6 ml) at reflux temperature for one hour. The solution was then cooled and ammonium hydrate 28 Bé (15 ml) was added with vigorous stirring. One hour later, after dilution with ethyl ether (300 ml) and filtration, 6-carboxamido-2'-isopropoxy-flavone (21 g; mp 267 - 270 °C) was obtained, which was treated with p-toluenesulfonyl chloride ( 37.5 g) in pyridine (33 ml) and dimethylformamide (160 ml) at 90°C for 8 hours. After cooling, diluting with water (1.1.5) and filtering, the collected precipitate was dried and washed with hot isopropyl ether (300 ml) to give 6-cyano-2<1->isopropoxy-flavone (15.6 g mp 172-175°C), which was then treated with sodium azide (33 g) and ammonium chloride (27 g) in dimethylformamide (120 ml) at 100°C for 4 hours. After cooling, diluting with water (600 ml), acidifying with concentrated hydrochloric acid and filtering, 6-(5-tetrazolyl)-2'-isopropoxy-flavone (11 g, m.p. 293-295°C) was obtained, after crystallization from chloroform /ethanol.

2'-isopropoxy-flavone-6-carbonyl chloride prepared as described above was treated with an excess of anhydrous ethanol at room temperature to give 6-carbethoxy-2'-isopropoxy-flavone, , m.p. 107-108°C.

Similarly, 6-carbethoxy-2-(2'-pyrazinyl)-chromone, m.p. 168-169°C obtained.

EXAMPLE 15

By proceeding in the same manner as described in Example 14, starting from 6-carboxamido-2-(3'-pyridyl)-chromone, prepared from the corresponding ethyl ester with gaseous ammonia in ethanol at 0°C for 6 hours, 6- (5-tetrazolyl)-2-(3<1->pyridyl)-chromonef M.p. 295°C (dec.) (yield = 85%) obtained.

By applying the same procedure, the following compounds were obtained: - 6-(5-tetrazolyl)-2-(2'-pyridyl)-chromone, m.p. >300°C (decomposition), I.R. (BKr): V NH (tetrazole) 3100 cm"<1>; 2700 cm"<1>; ^0=0 1620 cm<-1>; - 6-(5-tetrazolyl)-2-(2'-pyrazinyl)-chromone, m.p. > 310°C (decomposition), I.R. (KBr): ^c=0 (chromon) 1630 cm"<1>.

EXAMPLE 16

6-Carboxy-2<1->isopropoxy-flavone (6.3 g) suspended in benzene

(25 mL) was treated with thionyl chloride (1.8 mL) at reflux temperature for one hour. The solution was then evaporated to dryness under vacuum, and the residue was dissolved in 1,2-dichloroethane (45 mL) and treated with 5-amino-tetrazole (2 g) and sodium bicarbonate (2.7 g) with stirring at room temperature in 3 hours. The precipitate thus obtained was filtered, washed with water and crystallized from dimethylformamide to give 6-(5-tetrazolyl-carboxamido)-2'-isopropoxy-flavone (4 g; mp 275-278°C).

EXAMPLE 17

6-Carboxy-2'-isopropoxy-flavone (3.2 g) was treated with a warm aqueous solution containing sodium bicarbonate (800 mg). The small, undissolved portion of acid was filtered off and the clear solution was concentrated under vacuum almost to dryness. On treatment with acetone (200 ml), crystallization of the sodium salt of 6-carboxy-2'-isopropoxy-flavone (3.1 g; mp > 300°C) was obtained.

By an analogous procedure, the sodium salts of the following compounds were prepared:

- 6-carboxy-21-(2-methyl-propoxy)-flavone; m.p. > 300°C

- 6-carboxy-2'-(1-methyl-propoxy)-flavone; m.p. >300°C; - 6-carboxy-2'-(2-hydroxy-propoxy)-flavone; m.p. >300°C.

EXAMPLE 18

2<1->isopropoxy-flavone-6-carbonyl chloride (5.6 g), prepared according to Example 17, dissolved in anhydrous benzene (50 ml) was treated with diethylaminoethanol (4.2 ml) and triethylamine (1 ml) at room temperature for 4 hours. The benzene solution was washed with sodium bicarbonate (5%) and water, then evaporated

dryness. The residue was dissolved in acetone (100 ml), by adding the stoichiometric amount of concentrated hydrochloric acid, the precipitation of hydrochloric acid from the diethylaminoethyl ester of 6-carboxy-2'-isopropoxy-flavone was obtained. The compound (5.4 g, mp 215-217°C) was recovered by filtration and washed thoroughly with acetone.

Using the same procedure, the hydrochloride was

of the diethylaminoethyl ester of 6-carboxy-2-(2'-pyrazinyl)-chloro-

mon (m.p. 113-115°C) obtained.

Using the same method, the following compounds were obtained:

- 6-(2-N,N-dimethylamino-ethoxycarbonyl)-2,-isopropoxy-flavone, mp<p.> 71-73°C; - 6-(2-N,N-dimethylaniino-ethoxycarbonyl)-2-(2'-pyrazinyl)-chromone, m.p. 116-118°C.

EXAMPLE 19

Methyl 3-acetyl-4-hydroxybenzoate (6 g) in 100 ml of dioxane was

reacted with 2-isopropoxy-5-methyl-benzoyl chloride (10 g) in the presence of pyridine (10 ml) at room temperature for 16 hours. After pre-

dilution with water, the precipitate was extracted with ethyl acetate and the organic solution was washed with 5% NaHCO^ and water and then

evaporated to dryness to give methyl 3-acetyl-4-(2'-isopropoxy-5'-methyl-benzoyloxy)-benzoate (13 g, oil) which was dissolved in methyl ethyl ketone (200 mL) and treated with anhydrous potassium

carbonate (22 g) and stirred at reflux temperature for 4 hours.

After cooling, the reaction mixture was diluted in ice water and

extracted with ethyl acetate, and the organic solution was washed with water and evaporated to dryness. The rest (12.7 g)

was crystallized from methanol and thus gave 8.1 g of (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-5-methyl-benzoyl)-methane, melting point 85 - 86°C which was refluxed for 15 minutes with 30 ml 99% formic acid. After cooling and diluting with water, the precipitate was extracted with chloroform and the organic solution was washed with water until neutral and then concentrated to dryness. The residue was crystallized from methanol and gave 6.3 g of 6-carbomethoxy-2'-isopropoxy-5'-flavone, melting point 149 -

151°C which was hydrolysed with 1% solution KOH in 95% ethanol

(95 mL) at reflux temperature for 30 minutes. After cooling, the reaction mixture was acidified with 23 HCl to pH 3

and the precipitate was filtered off and washed with ethanol and water and thus gave 5.9 g of 6-carboxy-2'-isopropoxy-5'-methyl-flavone, melting point 209 - 210°C.

By proceeding analogously, the following compounds were prepared: 6-carboxy-2'-isopropoxy-3'-methyl-flavone, melting point 198 - 200°C, 6-carboxy-2'-isopropoxy-4<1->methyl- flavone, melting point 296 - 298°C, 6-carboxy-2'-isopropoxy-5<1->ethyl-flavone, melting point 203 - 205°C, 6-carboxy-2<1->isopropoxy-5'-propyl- flavone, melting point 236 - 237°C,

EXAMPLE 20

A solution of methyl 3-acetyl-4-hydroxy-benzoate (6 g) and methyl 2-methoxy-5-methyl-benzoate (12 g) in dioxane (40 ml) was slowly added with stirring at room temperature to a suspension of sodium hydride 50% (4.5 g) in dioxane (40 ml). The mixture was kept

with stirring for 3 hours at 80°C, cooled, then diluted with petroleum ether (100 ml) bg filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate.

The organic phase was washed with 5% potassium carbonate and water,

then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-(2-methoxy-5-methyl-benzoyl)-methane (7.9 g, mp 145 - 147°C) which was then refluxed -boiled for 15 minutes with 99% formic acid (28 ml). After cooling and dilution in water and filtration, the collected precipitate was crystallized from acetone to give 6-carbomethoxy-2'-methoxy-5'-methyl-flavone (6 g), mp 154 - 156°C, which was hydrolyzed with a 1 % solution of potassium hydroxide (100 mL) in 95% ethanol at reflux temperature for 30 minutes. The mixture was cooled, acidified with 23% HCl to pH 3 and the precipitate was filtered,

washed with 95% ethanol and water and thus gave after crystallization from ethanol 6-carboxy-2'-methoxy-5'-methyl-flavone (5.3 g), melting point 246 - 247°C.

EXAMPLE 21

Preparation of a salt

6-Carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester hydrochloride (5.95 g), prepared according to Example 21, was treated with an excess of 5% sodium carbonate at room temperature and the resulting free ester was extracted with ethyl acetate.

The organic solution was evaporated to dryness. The residue was crystallized from isopropyl ether to give 3.4 g of 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester (m.p. 76-78°C) which was dissolved in 50 ml of acetonitrile and treated with 0/93 g of maleic acid at room temperature for 1 hour.

After filtering the precipitate, 3.35 g of the maleate of the 6-carboxy-2<1-> isopropoxy-flavone-diethylaminoethyl ester (m.p. 158-164°C) were obtained.

EXAMPLE 2 2

27 g of (2-hydroxy-5-carboxy-benzoyl)-pyrazinoyl-methane was treated with 20 ml of HCl concentrated in 200 ml of acetic acid at the reflux temperature for 1 hour. After cooling, the precipitate was recovered by filtration and washed with water and then with hot ethanol to give 17.8 g of 6-carboxy-2-(2'-pyrazinyl)-chromone,

m.p. > 350°C.

By proceeding in the same way, the following compounds were prepared: - 6-carboxy-2-(2'-thienyl)-chromone, m.p. 301-304°C;

- 6-carboxy-2-(2,-furyl)_krt)irDnf <g>apm 330-332°CJ

- 6-carboxy-2-(2<1->pyridyl)-chromone, m.p. > 300°C; - 6-carboxy-2-(3<1->pyridyl)-chromone, m.p. > 350°C; - 6-carboxy-2-(4<1->pyridyl)-chromone, m.p. >350°C; - 6-carboxy-2-(6<1->methyl-2'-pyrazinyl)-chromone, m.p. 320°C (decomposition); - 6-carboxy-2-(5'-methyl-2<1->pyrazinyl)-chromone, m.p. 316-319°C;

EXAMPLE 23

13 g of (2-hydroxy-5-carboxy-benzoyl)-(2-isopropoxy-benzoyl)-methane was treated with 10 ml of HCl concentrated in 150 ml of ethanol at the reflux temperature for 1 hour.

After cooling, the precipitate was filtered, washed with water and hot ethanol to give 7.5 g of 6-carboxy-2'-isopropoxy-flavone, m.p. 209-211°C.

Similarly, the following compounds were obtained:

- 6-carboxy-2'-propoxy-flavone, m.p. 201-203°C; - 6-carboxy-2'-(2-methyl-propoxy)-flavone, m.p. 193-195°C; - 6-carboxy-2'-butoxy-flavone, m.p. 204-206°C; - 6-carboxy-2'-ethoxy-flavone, m.p. 225-227°C;

- 6-carboxy-2<1->methoxy-flavone, m.p. 265-267°C,

EXAMPLE 2 4

12 g of (2-hydroxy-5-carboxy-benzoyl)-(4-fluoro-benzoyl)-methane,

was treated with 15 ml of 57% HJ in 95 ml of acetic acid at the reflux temperature for 30 minutes.

After cooling, the precipitate was filtered, washed with water and hot ethanol to give 6/9 g of 6-carboxy-4'-fluoroflavone, m.p. 297-299°C.

Proceeding in the same way, the following compound was obtained:

- 6-carboxy-3'-fluoroflavone, m.p. 314-316PC.

EXAMPLE 25

By proceeding according to example 26 and starting with the suitable (2-hydroxy-5-carboxy-benzoyl)-cinnamoyl-methane derivatives, the following compounds were obtained: - 6-carboxy-2-(fl-phenyl-vinyl)-chromone, m.p. 273-275°C; - 6-carboxy-2-(a-methyl-1f-phenyl-vinyl)-chromone, m.p. 220-222°C; - 6-carboxy-2-[fl-(4'fluoro-phenyl)-vinyl]-chromone, m.p. >320°C; - 6-carboxy-2-[B-(3<1->pyridyl)-vinyl]-chromone, m.p. > 350°C; - 6-carboxy-2-[fl-(4 1 -methyl-phenyl)-vinyl]-chromone, m.p. >320°C.

EXAMPLE 26

9 g of [2-hydroxy-5-(5-tetrazolyl)-benzoyl]-pyrazinoyl-methane was

treated with 90 ml of formic acid (99%) at the reflux temperature for 3 hours.

After cooling, the precipitate was filtered, washed with water and hot ethanol to give 4.8 g of 6-(5-tetrazolyl)-2-(2'-pyrazinyl)-chromone, m.p. > 310°C (decomposition).

Proceeding in the same way, the following compounds were obtained: 6-(5-tetrazolyl)-2'-pyridyl-chromone, m.p. >300°C (decomposition), I.R. (KBr): V NH(tetrazole 3100 cm"<1>; 2700 cm"<1>; V C=0 1620 cm"<1>; - 6-(5-tetrazolyl)-2'-isopropoxy-flavone, m.p. 293-295°C.

EXAMPLE 27

A solution consisting of 2-N,N-diethylamino-ethyl 3-acetyl-4-hydroxy-benzoate (8.6 g) and methyl 2-isopropoxy-benzoate (12 g)

in dioxane (50 mL) was slowly added with stirring at room temperature to a suspension of sodium methoxide (5.1 g) in dioxane (20 mL). The mixture was heated at 80°C for 5 hours, then diluted with water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with NaHCO3 (5%) and water, then evaporated to dryness and crystallized from ethanol to give [2-hydroxy-5-(2-N,N-diethylamino-ethoxy-carbonyl)-benzoyl]- (2-isopropoxy-benzoyl)-methane (9.1 g), which was then refluxed for 30 min with formic acid (99%) (45 mL). After cooling and dilution in water and filtration, the collected precipitate was crystallized from isopropyl ether to give 6.9 g of 6-(2-N,N-diethylamino-ethoxycarbonyl)-2 1-isopropoxy-flavone, m.p. 76-78°C. This product was then dissolved in acetone

(100ml); On addition of the stoichiometric amount of HC1 (conc.), the corresponding hydrochloride precipitated, which was recovered by filtration and carefully washed with acetone. On

in this way, 6.5 g of 6-(2-N,N-diethylamino-ethoxycarbonyl)-2'-isopropoxy-flavone hydrochloride, m.p. 215-217°C obtained.

By proceeding in the same way, the following compound was obtained: - 6-(2-N,N-dimethylamino-ethoxycarbonyl)-2'-isopropoxy-flavone, m.p. 71-73°C;

EXAMPLE 2 8

By proceeding according to example 27 and starting from the suitable 2-N,N-dialkylaminoethyl esters of 3-acetyl-4-hydroxybenzoate and methyl pyrazinoate, the following compounds were obtained: - 6-(2-N,N-dimethylamino -ethoxycarbonyl)-2-(2'-pyrazinyl)-chromone, m.p. 116-118°C; - 6-(2-N,N-diethylamino-ethoxycarbonyl)-2-(2<1->pyrazinyl)-chromone, m.p. 113-115°C.

Claims (1)

Analogous process for the preparation of new therapeutically active 5:6-benzo-4-pyrone derivatives of the general formula (I) where: n^ is 0 or 1, R, which is in the 6- or 7-position, is COOR^, where R 13 is hydrogen or a C1~C^2 alkyl9"ruPPe' which may be unsubstituted or substituted with the group wherex each of R^q and R^ independently is hydrogen or C^-Cg alkyl, or R3 is hydrogen or C^-Cg alkyl, R^, is hydrogen or C^-Cg alkyl, each of R^, R^ and Rg is equal or different and are: hydrogen, fluorine, where R^0 and R^ are as indicated above, a residue -(0) -R' , where m is 0 or 1, and R'-,-, is a C_-C, 0 m 13 ^ 13 212 alkenyl or a C^^-C 2 alkyl group optionally substituted with an -ORl 4 group, where R 14 is hydrogen or a C^-C 8 alkyl group, X is phenyl, furyl, thienyl, pyridyl or pyrazinyl, and pharma -chemically acceptable salts thereof, provided that when at the same time X is phenyl, n^^ is 0 and , R&, R? and Rg are all hydrogen, R is not a free carboxy group, characterized in that one (a) cyclizes a compound of formula (Jl) wherein R, r3, r5, Rg, Rg and x are as above, (b) reacts a compound of the general formula (III) where R and R5 are as previously indicated, with an aldehyde of the general formula (IV) wherein Rg, Ry, Rg and X are as previously indicated, giving compounds of formula (I) wherein n^ is 1 and R-^ is hydrogen, (c) dehydrogenates a compound of general formula (V) wherein n^, R, R^, R^, Rg, R7, Rg and X are as previously indicated, (d) cleaves a hydrogen halide from a compound with the general formula (VI) wherein one of M is hydrogen and the other is halogen, R, R,-, Rg, R^,, Rg and X are as previously indicated, giving compounds of general formula (I), wherein n^ is 0, and, if desired, the transfer compound of the general formula (I) into another compound of the general formula (I) by known methods, and/or, if desired, the transfer compound of the general formula (I) into a pharmaceutically acceptable salt thereof, and/or, if desired, dissolves an obtained mixture of optical isomers into the individual isomers.